Our laboratory has a strong interest in pharmacogenetics. We have integrated pharmacogenetics/pharmacogenomics (PG) research in our drug development efforts to evaluate the impact of genetic variants on drug metabolism, PK, response and toxicity as well as to understand the contribution of inter-individual variation in clinical outcomes in therapies with an already narrow therapeutic window. We have established a molecular link between these polymorphisms and their phenotype as it relates to drug treatment. Most of our work has been focused on genetic variations in drug metabolism and transporting candidate genes such as ABCB1 (P-glycoprotein, MDR1), ABCG2 (BCRP), SLCO1B3 (OATP1B3, OATP8), CYP3A4, CYP3A5, CYP1B1, CYP2C19, CYP2D6, UGT1A1, UGT1A9 and several others. Drug transporters mediate the movement of endobiotics and xenobiotics across biological membranes in multiple organs and in most tissues. As such, they are involved in physiology, development of disease, drug pharmacokinetics, and ultimately the clinical response to a myriad of medications. Genetic variants in transporters cause population-specific differences in drug transport and are responsible for considerable interindividual variation in physiology and pharmacotherapy. Thus, we are interested in studying how inherited variants in transporters are associated with disease etiology, disease state, and the pharmacological treatment of diseases. We are also interested in non-candidate gene approaches where large numbers of polymorphisms are explored to establish a relationship with clinical outcome, and experiments are conducted to validate potential causative alleles resulting from exploratory scanning. We have worked with Affymetrix to beta-test the DMET chip that contains 1,936 genetic variations in 231 drug disposition genes, and have established a clinical trial where patients treated at the NCI will be genotyped with the DMET chip to explore potential links between these genes and outcomes from several cancer therapies. We are currently making progress in validating the results from the initial DMET chip experiments. While many of these studies have been conducted in order to explain some of the genetic influence on pharmacokinetic variability, we also have a strong interest in clarifying genetic markers of pharmacodynamics and therapeutic outcome of several major anticancer agents since this field has been rather poorly studied. We have studied the pharmacogenetics assessments of many anticancer agents including recently mithramycin, belinostat, docetaxel/lenalidomide/bevacizumab combination, olaparib/carboplatin combination, carfilzomib, and azathioprine. The combination of carfilzomib, lenalidomide, and dexamethasone (CRd) has induced deep responses in patients with newly diagnosed multiple myeloma. While vascular endothelial growth factor (VEGF) pathway polymorphisms have been associated with clinical outcomes for antiangiogenesis agents, we explored associations between such polymorphisms and CRd clinical response. The VEGF-1498CT (rs833061) and VEGFR2 V297I (rs2305948) were associated with CRd response, whereas VEGF-1498CT and VEGFR2 Q472H (rs1870377) were associated with minimum residual disease negativity. As these SNPs were not associated with disease parameters (e.g., plasma VEGF, albumin, or beta-2-microglobin concentration), data suggest these SNPs may be markers of CRd response. In our continuing collaborative effort with the University of Maryland, we were involved in conducting a pharmacogenomics study on clopidogrel, one of the most commonly used therapeutics for the secondary prevention of cardiovascular events in patients with acute coronary syndromes. Considerable interindividual variation in clopidogrel response has been documented, resulting in suboptimal therapy and an increased risk of recurrent events for some patients. We performed the first genome-wide association study of circulating clopidogrel active metabolite levels in 513 healthy participants to directly measure clopidogrel pharmacokinetics. We observed that the CYP2C19 locus was the strongest genetic determinant of active metabolite formation (P=9.5x10). In addition, we identified novel genome-wide significant variants on chromosomes 3p25 (rs187941554, P=3.3x10) and 17q11 (rs80343429, P=1.3x10), as well as six additional loci that showed suggestive evidence of association. Four of these loci showed nominal associations with on-clopidogrel ADP-stimulated platelet aggregation. Evaluation of clopidogrel active metabolite concentration may help identify novel genetic determinants of clopidogrel response, which has implications for the development of novel therapeutics and improved antiplatelet treatment for at-risk patients in the future.